EXCEED THE SPACE PROVIDED. Metal ion sensory mechanisms are critical for cellular responses to essential and toxic metals alike. Studies of microbial metalloregulatory systems serve as a starting point for understanding cell biology of metals in humans. A general but controversial mechanism for iron-responsive derepression has been proposed but is as of yet unresolved. Mechanistic studies of these mercury and iron sensor proteins are now beginning to provide insights into zinc and copper-responsive metalloregulation. The E. coli ZntR gene, a recently discovered member of the MerR family, encodes a zinc-specific metalloregulatory protein that controls expression of zinc export machinery. Its counterpart, the Zur protein, is a member of the Fur family which exerts zinc-responsive control over the expression of zinc uptake machinery. Together these genes thus govern zinc uptake and export, ensuring that cells neither starve for, or made sick by increases zinc concentration. This proposal focuses on energetic and structural aspects of metal recognition and in the allosteric switching mechanism. MerR controls transcription in an unprecedented manner: metal-protein interactions induce distortions in DMAstructure that make it a better template for transcription. By comparing the positive control mechanism for other family members such as ZntR, a comprehensive test of this DMA distortion mechanism is possible. Positive control mechanisms are poorly understood and yet are of fundamental importance in understanding the molecular basis of genetic regulation. The molecular basis of heavy metal recognition in both the ZntR, Zur and Fur systems will be probed at the biopolymer and coordination chemistry levels. The structure, function and energetic insights of these new stress responsive transcription factors to develop molecular mechanisms and a deeper understanding of transition metal cell biology.